Preparation of hydantoins from hydrozones



v PREPARATION OF OINS FROM HY DRGZGN ES No Drawing. ApplicationSeptember 17, 1957 Serial No. 684,416

10 Claims. c1. z60-309.s

This invention relates to the preparation of hydantoins, and is moreparticularly concerned with the conversion of hydrazones to hydantoins.1

'It is known that aldehydes and 'ketones can be converted to hydantoinswith ammonium carbonate and cyanides, and that the resulting hydantoinscan readily be hydrolyzed to form valuable amino acids. Suitable methodsare disclosed in the publications, H. T. Bucherer et al., Uber dieBildung substituierter Hydantoine aus Aldehyden und Ketonen, J. Prakt.Chem, 141; 5-43 (1934), and W. Gebhardt, Uber Hydantoine,Thiohydantoine, Sulfothiazolidonund Sulfothiazolidoniminderivate, diss.Technischen Hochschule Munchen, 38 pages (1935). However, thepreparation and isolation of aldehyde or ketone starting materials ofsuitable stability and reactivity for the conversion has imposed seriouspractical limitations on the .hydantoins and corresponding amino acidswhich canbe preparedcommercially.

It is an object of this invention to provide a more generally usefulprocess for preparing hydantoins which does not dependupon isolation ofaldehyde or ketone starting reactants. Other objects will becomeapparent from the specification and claims. V

In accordance with this invention aldehyde or -ketone hydrazones of thegeneral formula is a group corresponding to the aldehyde or ketoneportion of th'ename and Ris' a stable substituent attached,

by carbon, e.g., carbamyl, thiocarbamyl, oxamyl, ,sirnple acyl andalkyl, aralkyl orarylhydrocarbon radicals, are readily convertedtohydantoins byreaction in a solution containing ammonium ions,carbondioxide or carbonate ions and cyanide ions. The reaction mechanismis not understood, but the overall result is as follows:-

process of this inn w S are 2, vention includes the aldehyde and ketonehydrazones wherein the above R and R! are selected from'the groupconsisting of hydrogen, hydrocarbon substituents, substituentscontaining oxygen, hydrolytically stable halo gen, nitrogen or sulfur inan otherwise hydrocarbon group, and substituents wherein R and R" arejoined to form an alicyclic ring of 5 to 6 carbon atoms whichincludesthe alkylidene carbon of the above formula; Included are alkyl,aralkyl and a'ryl substituent groups and such groups having a hydroxyl,lower 'alkoxy, lower acyl or halogen substituent on a carbon atom, alsoheterocyclic substituents containing a single heteroatom of oxygen,nitrogen or sulfur in a heterocyclic ring. a

In the process of this invention the .hydrazone; preferably an aldehydeor ketone semicarbazone, thiosemica'rbazone, alkylhydrazone orarylhydrazone, is heated in an inert polar solvent, preferably water oralo'wer alcohol or a mixture thereof, containing ammonium ions,carbonate ions and cyanide ions. Ammonium carbonate and-hydrogen cyanideare the most convenient sources of the required ions,-but othermaterials can obviously be used to form these ions in solution.Thus-carbon dioxide and ammonia orvarious ammonium salts can be addedseparately, in place of ammonium carbonate,:.and metal cyanides can beused in place of hydrogen cyanide. Solid carbon dioxide can be added toincrease the concentration from the reaction.

of carbon dioxide in solution. The addition of a small amount of sodiumhydrogen sulfite or other bisulfite will usually increase the yield, butis not essential. The yield may also be improved by complete exclusionof oxygen A reaction temperature of about 40 C. to about 220 C. issuitable, with pressure being required at the higher temperatures. Theoptimum'reactiontemperature is to C. At about 100 C. the reaction isusually complete in about 3 to 4 hours. The relatively insolublehydantoin product can be separated from the reaction mixture byfiltration. The yield can frequently be improved by concentrating thefiltrate or salting out soluble product with neutral salts, e.g.,

sodium sulfate. The'hydantoin is purifiedby reerystallization from wateror other solvent.

Preferredprocess conditions will be shown in the examples, whichillustrate specific embodiments of the in vention. Parts refers toparts'by weight.

'EXAMPLE I A pressure reactor was charged with 4.5 parts 'n-butyrAseco'nd crop of 0.8 part of crude product was recovered bypartiallyevaporating the 'originalfmothe'r liquor, giving a total recovery of46.5%. i 1

- 1 The n-butyraldehyde semicarbazon used in the above example'may beprepared by charging an autoclave WithS' parts -n butyrOnitriIe, 21parts semicarbazide hydrochlo ride,'15 parts sodium acetate, 5 partsRaney. nickel cata j lyst, 100 partswater and hydrogen at'100atmospheres pressure. After 3 hours at room temperature-the reac- :tionmixture is filtered and the filtrate is partially" evap' orated tocrystallize out the butyraldehyde semicarbazone The distinctive meltingpoint identified the product 'as 5-n'-propyl hydantoin,

from water to give a melting point of 955 C.

EXAMPLE II A pressure reactor was charged with 10 parts3-indoleacetaldehyde semicarbazone, 7.5 parts ammonium carbonate and 70parts water. The reactor was flushed with nitrogen and then 1.5 parts ofhydrogen cyanide was introduced. The reactor was closed and heated at100 C. for 4 hours. The reaction mixture was then cooled to5 C. and thewhite precipitate formed was separated by filtration. This product wasrecrystallized from water to give 7.0 parts of product melting at 216.5-217.0 C. Itwas identified as being the known compound,S-(S-indolylmethyl)-hydantoin, by elemental analysis, infrared analysisand paper chromatographic analysis. Therefore the reaction gave a 65%yied of the 5-,(3-indolylmethy1)-hydantoin represented by thestructuralaformula,

Nil-C6 tryptophan,

CHz-(iiH-C O OH One part of 5-(3-indolylmethyl)-hydantoin and 14 partsof an aqueous solution containing a 4% concentration of sodium hydroxidewere heated under pressure at 150 C. for 30 minutes. The reactionmixture was neutralized with acid and the precipitated DL-tryptophan wasseparated by filtration, washed'and dried. The melting point of 283C(corresponded to the known melting point for substantially pureDL-tryptophan.

Semicarbazide is formed along with '5-(3 indolylmethyl)-hydantoin andcan be recovered as semicarbazide hydrochloride for use in forming thesemicarbazone starting material. The solutions remaining afterrecovcryof the hydantoin were evaporated to dryness under reduced pressure,below 37 C., to remove 'unreacted hydrogen cyanide and ammoniumcarbonate. The residue was extracted with 45 parts of distilled water at0 C. The aqueous solution was evaporated to dryness, leaving a lightbrown resin. This resin was extracted with a total of 30 parts ofabsolute ethanol. The addition of anhydrous hydrogen chloride to. thisextract precipitated 3.3 parts of crude semicarbazide hydrochloride,corresponding to 63.4% recovery of the Semicarbazide used in thestarting material. Recrystallization of this crude product from aqueousethanol gave a product melting at 170173 C. when heated rapidly, whichagrees with Calculated: C, 61.09; H, 5.59; N, 25.92. Found: C, 60.68; H,5.52; N. 25.98, 25.48.

This product is believed to exist in two geometrical isomeric forms(presumably syn and anti forms), because it could be separated intoacrystalline form melting at about 188 C. and a crystalline form meltingat about 152 C. which is converted to the higher melting form by heat.Since either can be used as the starting material in Example II, it isnot necessary to separate the two forms from the mixture ordinarilyobtained.

EXAMPLE III A reaction mixture was prepared by adding, to anappropriately sized pressure vessel, 6.5 parts benzaldehydesemicarbazone, 5.5 parts ammonium carbonate, 0.7 part liquid hydrogencyanide, 1 part sodium acid sul fite, 80 parts methanol and 20 partswater. The mixture was heated at 100 C. for 4 hours. The solvent wasevaporated and v2 parts of S-phenylhydantoin, having a meltingpoint of183-l85 C., was recovered from the residue by extraction with alcohol.and recrystallization.

The melting point and the following .elementalanalysis identifiedtheproduct asthe monohydratez' Calculated: C, 55.7; H, 4.1; N, 14.4. Found:'C, 56.2; H, 4.7; N, 14.8.

The benzaldehydesemicarbazone starting material for Example III may beprepared as described in Example I of the previously referenced Germanapplication Serial No. K 24529.

7 EXAMPLE IV A mixture of 10 parts cyclopentanone thiosemicarbazone, 11'parts ammonium carbonate, 1.5 parts hydrogen cyanide, 3.0 parts sodiumbisulfite, 50 parts water and 50 parts ethanol was heatedin a pressure.vessel for 4 hours at 120 C. The reaction mixture was cooled andfiltered to remove crystals of thiosemicarbazide, of which 2.6 partsmelting at 181182. C. was recovered. The filtrate was evaporated todryness under vacuum, leaving 9.6 parts of a crystalline mass. This masswas extracted CHr-CH: (JO-NH l Hg-Ca NH- 0 Calculated analysis: C,54.5;LH, 6.5; N, 18.2. Found (first crop): C, 54.4; H, 6.4; N, 18.2.Foundtsecond crop): C, 54.9; H, 6.7; N, 18.4.

I The cyclopentanone thiosemicarbazone starting material in Example IVmayv be prepared as described by .Baird, Burns and Wilson, J. Chem.Soc., 1927, pages authentic :samples of Semicarbazide hydrochloride. The

product was used to prepare semicarbazones of benzaldehyde andcyclohexanone'which were verified by melting a point and mixed meltingpoints with authentic samples of.

the semicarbazones.

The S-in doleacetaIdehyde semicarbazone' used as .a starting material.in,.Example II has been prepared as described in Example'3 ofPlieninger, German applica- EXAMPLE V A suitably sized pressure vesselwas charged with 11.4 parts n-butyraldehyde phenylhydrazone 11 partsammonium carbonate, 1' part sodium hydrogen sulfite, 3 parts hydrogencyanide, 40 parts methanol and 40 parts water. The reaction mixture washeated at C. for 6 hours and the volatile materials were then evaporatedunder partial vacuum: The.residue,:which was part oiLandflpartcrystalline solid, was filtered and the solid was copiously washed withether to remove theoil. The solid was redissolved'in methanol, thesolution was evapo rated to dryness, and the solid was'again washedcopiously with ether to yield 3.4 parts of yellow crystalline-solid. I

7 After recrystallization from water, a melting point of 135- 137 C. wasobtained, whichidentifiedtheproduct as S-n-propyl hydantoin. 5 It wasfurther identified by taking the mixed melting point with an authenticsample of the compound. Y I

The n-butryraldehyde phenylhydrazone used in the above example may beprepared as described in Huntrew and Mulliken, Identification of PureOrganic Com pounds, Order I (John Wiley and Sons, 1941).

EXAMPLE VI A pressure reactor was charged with 7.8 parts 3-in-.doleacetaldehyde phenylhydrazone, 25.0 parts ammonium carbonate, 8.2parts sodium bisulfite and 4.3 parts hydrogencyanide in 350 partsdistilled water and 5 parts methanol. The mixture was heated for 4 hoursat 100 with shaking. The reaction mixture was cooled to 0-5 anddischarged. The tube was rinsed with 100. parts methanol which wascombined with the hydrogenation charge.- The combinedmixture wasevaporated to dryness and the residue extracted with 50 parts water.5-(3-Indolylmethyl)-hydantoinremained behind as an undissolved residue.After air-drying it amounted to 5.0 parts EXAMPLE VII A pressure reactorwas charged with 9.9 parts l-acetyl- S-indoleacetaldehydephenylhydrazone, 25.0 parts am- .monium carbonate, 8.2 parts sodiumbisulfite and 4.3 parts hydrogen cyanide in 350 parts distilled waterand 5 parts methanol. The mixture was heated for 3.5 hours at 100 withshaking. The reaction mixture was cooled to 05 and discharged. The tubewas rinsed with 130 parts methanol which was combined with thehydrogenated charge. The combined mixture was evaporated to dryness andthe residue extracted with 60 parts water. S-(3-indolylmethyl)-hydantoin remained behind as an undissolved residue.After air-drying it amounted to 5.5 parts and melted at 214222 C. Thismaterial did not depress the melting point of an authentic sample of5-(3-indolylmethyl) -hydantoin.

The 1 acetyl 3 indoleacetaldehyde phenylhydrazone used in thisexperiment was prepared by the reaction of 1-acetyl-3-indoleacetaldehydewith phenylhydrazine.

EXAMPLE VIII A pressure reactor was charged with 2.4 parts l-acetyl-3-indoleacetaldehyde semicarbazone, 6.0 parts ammonium carbonate and 1.5parts hydrogen cyanide in 60 parts Water and heated at 100 for 4 hourswith shaking. The reaction mixture was cooled to 0-5 C. and discharged.5-(3-indolylmethyl)-hydantoin which has separated out was collected bysuction filtration, washed with cold water and air-dried. It mounted to1.3 parts and melted where R is an alkyl group and R" is hydrogen or analkyl group which is the same or different from that of R. The procedureillustrated for'n-butyraldehyde; semiphenylhydrazone used in thiscarbaz'one is suitable for any of these compounds. Thusn-propionaldehyde semicarbazone (M.P. 89 C.) can be substitutedinExample I to give S-ethyl hydantoin. Likewise acetone semicarbazone (MP.187' C.) can be substituted to give 5,5-dimethyl hydantoin and methylethyl ketone semicarbazone (M.P. C.) can be substituted to give 5methyl-5-ethyl hydantoin.

' Example H has illustrated the formation of hydantoins fromsemicarbazones of the formula wherelR' is a group attachedby carboncontaining a single heteroatom of oxygen, nitrogen or sulfur in anotherwise hydrocarbon group, and R is hydrogen or an alkyl group. .ASadditional examples, instead of the 3- indoleacetaldehyde semicarbazoneof Example II, .furfural semicarbazone (M.P. 202 C.) can be substitutedto giVeS-a-furyl) hydantoin and 3-indo1ealdehyde semicar-' bazone can besubstituted to give 5-(3-indole)-hydantoin.

Example HI has illustrated the formation of hydantoins" fromsemicarbazones of the formula where R is a hydrocarbon group containingan aromatic ringand R" is hydrogen or an alkyl group. As additionalillustrations, ,a-tolualdehyde semicarbazone (M.P. 156

C.) can ,besubstituted to give S-benzyl hydantoinan'd acetophenonesemicarbazone (M.P. 198C.) can be substituted to give 5methyl-5-phenylhydantoin. Example -IV, has illustrated the reaction where R' of theabove Substitution of] cyclohexanone semicarbazone (M.P. 166 C.) givesspiro formula is an alicyclic hydrocarbon.

[cyclohexane-l,5'-hydantoin] by the same procedure.

Example V has illustrated that the same reaction takes place when,instead of the carbamyl group of the above semicarbazones, other stablegroups are present. Illustrations of such groups are aryl as inbutyraldehyde phenyl hydrazone, alkyl as in benzaldehyde propylhydrazone, acyl as in benzaldehyde acetyl hydrazone, and oxarnyl as inindoleacetaldehyde semioxamizide.

.Ihe process of this invention is of particular importance inthe'formation of hydantoins for conversion to aminoacids as illustratedin Example II. A similar procedure can be used to prepare otheraminoacids as set forth in the following table:

Preparation of qminoacids Aldehyde Substituent on Hydantoin Aminoacid bysemicarbazone Hydrolysis 1--- Formaldehyde... None Glycine 2.-.Acetaldehyde-. CH;. Alanine. 3--- 2-Hydroxypro- CHBCH OCO0H3) Threonine.

pionaldehyde (as acetic acid ester). 4 iso-Vuleraldehyde. (CH3)zCHCHz-Leucine. 5... Z-IA/Irghglbutral- CH3CHzCH(CH3)- Isoleucine.

e y e. t 6.-- Valeraldehyde CHaCHzCHzCHz- Norleueine. 7iso-Butyraldehyde (CH3):CH- Valine.

s--. a-TolualdehydeoH,- Phenylalanine.

9 p-Hydroxy-atolualdehydenu H0 CHz-... Tyrosine.

10-- 2-Hydroxyacetal- HO-OHP Serine.

dehyde. 11.- B-Methylrner- CHsSCHgCHa- Methionine.

captopropionaldehyde. 12-- 4-Aminobutyra1- HnN-CHzGHgCHP Ornlthine.

e y e. 13-- 5-Aminovaleral- H2N-CH2CHzCH2CH2.---- Lysine.

dehyde.

Since many diiferent embodiments ofthe'invention;

prises reacting an aldehyde hydrazone, 'having a single hydrogen of thesecond nitrogen substituted .by a stable substituent attached bycarbonof the substituent, with ammonium ions, carbonate. ions andcyanide ions in solution in an inert polar liquid solvent at-40 to 220C.

3. The process for producing a hydantoin which comprises reacting aketone hydrazone, having a single hydrogen of the second nitrogensubstituted by a stable substituent attached by carbon of thesubstituent, with ammonium ions, carbonate ions and. cyanide ions in.

solution in an inert polar liquid solvent at 40 to 220 C.

4. The process of producing a hydantoin which comprises heating areaction mixture of an aldehyde semicarbazone and a solution containingammonium ions,

carbonate ions and cyanide ions in an inert polar liquid solvent at 40to 220 C., and recovering the hydantoin product.

The process for producing a'hydantoin which comprises heating a reactionmixture of a ketone semicarbazone and a solution containing ammoniumions, carbonate ions and cyanide ions in an inert polar liquid solventat 40 to 220 C., and recovering the hydantoin product.

8- .6. The process for producing a hydantoin which comprises'heating areactionmixture of a hydrocarboncarboxaldehyde semicarbazone and asolution containing ammonium ions, carbonate ions and cyanide ions inaninert polar liquid solvent at 40 to 220 C., and recovering thehydantoin product.

7. The process for producing a hydantoin which comprises heating areaction mixture of 3-indoleacetaldehyde semicarbazone and a solutioncontaining ammonium ions, carbonate ions and cyanide ions in an inertpolar liquid solvent at 40 to 220 C., and recovering the hydantoinproduct.

.8. The process for. producing a hydantoin which comprises heating areaction mixture of an aralkanal semi- 'carbazone and a solutioncontaining ammonium ions,

carbonate ions andcyanide ions in an inert polar liquid solvent.at:40 to220 C., and recovering the hydantoin product. a

9. The'process for producing a hydantoin which comprises heatingareaction mixture of .a'cycloalkanone semicarbazone and a solutioncontaining ammonium ions, carbonate ions and cyanide ions in an inertpolar liquid solvent at 40 to 220 C., and recovering thehydantoinproduct.

10. The process for producing a hydantoin which comprises heating areaction mixture of a hydrocarboncarboxaldehyde phenylhydra zone and asolution containing ammonium ions, carbonate. ions and cyanide ions inan inert polar liquid solvent at 40 to 220 C., and recovering thehydantoin product.

References Cited in the file of this patent 'Plieninger et al.': Chem.Ber., vol. 89, p. 276 (1956). Brown et al.: J. Chem. Soc, vol. 1952, pp.3172-6.

1. THE PROCESS FOR PRODUCING A HYDANTOIN WHICH COMPRISES REACTING AHYDRAZONE, HAVING A SINGLE HYDROGEN OF THE SECOND NITROGEN SUBSTITUTEDBY A STABLE SUBSTITUENT ATTACHED BY CARBON OF THE SUBSTITUENT, WITHAMMONIUM IONS, CARBONATE IONS AND CYANIDE IONS IN SOLUTION IN AN INERTPOLAR LIQUID SOLVENT AT 40* TO 220*C.